Abstract
The ABC transporter, Mrp4, transports the sulfated steroid DHEA-s, and sulfated bile acids interact with Mrp4 with high affinity. Hepatic Mrp4 levels are low, but increase under cholestatic conditions. We therefore inferred that up-regulation of Mrp4 during cholestasis is a compensatory mechanism to protect the liver from accumulation of hydrophobic bile acids. We determined that the nuclear receptor CAR is required to coordinately up-regulate hepatic expression of Mrp4 and an enzyme known to sulfate hydroxy-bile acids and steroids, Sult2a1. CAR activators increased Mrp4 and Sult2a1 expression in primary human hepatocytes and HepG2, a human liver cell line. Sult2a1 was down-regulated in Mrp4-null mice, further indicating an inter-relation between Mrp4 and Sult2a1 gene expression. Based on the hydrophilic nature of sulfated bile acids and the Mrp4 capability to transport sulfated steroids, our findings suggest that Mrp4 and Sult2a1 participate in an integrated pathway mediating elimination of sulfated steroid and bile acid metabolites from the liver.
Highlights
The ABC transporter, Mrp4, transports the sulfated steroid DHEA-s, and sulfated bile acids interact with Mrp4 with high affinity
The farnesoid X receptor (FXR)1 contributes to bile acid homeostasis by regulating bile acid biosynthesis and controlling the expression of the major
Hepatic MRP4 and Sult2a1 Are Up-regulated by CAR Activators—We previously demonstrated that hepatic Mrp4 is upregulated as a compensatory response when FXR-null mice are challenged with cholic acid and after bile duct ligation [11]
Summary
Cyp3a11 Cyp2b10 Cyp2B6 Cyp3A4 Mrp Mrp Mrp MRP4 Mrp Bcrp Sult2a1 SULT2A1 Sult1a2 GAPDH. GCCTGGATTCTAAGCAGAAGC AGGAGAAGTCCAACCAGAACG TCCTTTCTGAGGTTCCGAGA CCAAGCTATGCTCTTCACCG GTCATCACTATCGCACACAG CGCTCTCAGCTCACCATCAT GGTTGGAATTGTGGGCAGAA CAGTACCTCAAAGCTGCAAGTC CTGGCTGGAGGACCTGTTGTT CCATAGCCACAGGCCAAAGT CTGGCTGTCCATGAGAGAAT GATCACGAGGTCAGGAGACT CTCCACCTCGATGAACAGAAC ACCACAGTCCATGCCATCAC a The gene names in all capital letters indicate nucleotide sequences derived from their human genes
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